PONE-D-21-09895

The economic burden of breast cancer due to physical inactivity in Brazil

PLOS ONE

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Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

Reviewer #5: Yes

Reviewer #6: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

Reviewer #6: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript "The economic burden of breast cancer due to physical inactivity in Brazil" study the economic impact of physical inactivity and breast cancer to Brazilian healthcare system. The study has merit and was written. However, I have some comments to the author.

Major comments:

1) There is only one author in the study? If is true, the sentence “These authors contributed equally to this work” in the first page make no sense.

2) The correlation between mean hospitalization cost and healthcare quality and access index is weak both in women aged 20-59 years and in those aged ≥60 years (rho = 0.37, p = 0.04 and rho = 0.43, p = 0.02) (figure 1 and 2). Besides some Brazilian estates showed a higher cost and higher access index, this is not direct correlated in the country. This should be clear in results and discussion.

3) In the discussion, lines 353 to 355 “The cost for the implementation of this program varies from R$ 80.000,00 (US$ 266,400.00) to R$ 180.000,00 (US$ 599,400.00) and ….”. The values in Real and Dollar should be revised in this sentence and perhaps in all text.

Minor comments:

1) Values of rho and p should be corrected. For instance: rho = .37, p = .04 to rho= 0.37, p = 0.04

Reviewer #2: I found that the article is well written. The content is interesting and well elaborated.

I found same minor errors that should be seen.

LIne 62 probably the number in euros is wrongly written.

Line 185 the term PAF was used in line 251 the term FAP was used for the same meaning

Line 342 is this phrase correct?

would be € 133,074, which is equivalent to approximately US$ 151,000,000

Line 354

implementation of this program varies from R$ 80.000,00 (US$ 266,400.00) to R$ 354 180.000,00 (US$ 599,400.00)

Reviewer #3: The study is important to added the information about the correlation about a breast cancer and economic costs in populous country such as brazil. The Datasus is a main source of data health from Brazilian`s population. This study have not study design, and the authors did not declare the conflict of interest.

Please see attachment.

Reviewer #4: General comments: The article has an exciting and very current theme. Economic analyzes in low- and middle-income countries are always welcome. Three methodological issues are central. The first question refers to the option of the authors to use a survey of the prevalence of risk factors that is not nationally representative to build a fraction attributable to be applied nationally. The second question concerns using only direct hospital expenses and highlighting in the title that an analysis of the economic burden is a broad concept. The third and last concerns the questionable contribution of the correlation analysis between attributable expenditure and the Healthcare Access and Quality (HAQ) Index.

Specific comments: 1. Although the article's title refers to economic burden in Brazil, data from Vigitel were used, which is a telephone survey with representation only for the 26 capitals and DF and not for Brazil; 2. The economic burden seems a broad term. The author only analyzed the hospital expenses of the public health system; 3. It was unclear why choosing the analysis period between 2015 and 2017; 4. It was also unclear why analyzing the correlation between expenditures and conditions of access and quality of services (HAQ) in the states; 4. It seems that the approval of CONEP was from the telephone survey research (Vigitel) and not from the study carried out; 5.What is the purpose of calculating the standardized rate of hospitalization for breast cancer; 6. the value of RR 1.40 used was not found in the reference text; 7. The example used in the discussion (lines 336-344) does not seem suitable for the discussion section once it was a foreign factual experience; 8. Review the dollar amounts in lines 352-355; 9. The reference used in lines 358-370 also does not seem adequate since an analysis of the attributable fraction of expenses by type (recreational, occupational, transport, at home) was not performed. The values marked in the article were not found in the original 10. Clarify the justification pointed out in lines 408-412; 11. The quality of life and mental well-being are considered non-measurable; why? Lines 412-416; 12. In the study's limitations, there was no mention of the issue of temporal GAP between exposure to the risk factor and the outcome. This question has not been considered, although other research groups on attributable fraction consider it very relevant; 13. I could not access reference #38, review doi; 14. Lines 425-426 reinforce that attributable expenditures were carried out using prevalence data from the state's capitals. Wouldn't that be a limitation? 15. No analysis was made of the correlation between expenditure attributable to physical inactivity and the HAQ index. Why? since the rho values are relatively low.

Reviewer #5: The introduction section is so long. Along the stretch between 62 and 81 lines are highlighted some studies with cost estimates widely different, limiting the cross-countries comparison. Sugiro excluir a maior parte e/ou transferir uma parte para a discussão. I suggest deleting most of this and/or transferring a part to the discussion.

It is not clear which is the study design.

The authors argue that “For all Brazilian states, the quality of data from DATASUS is considered high and close to high-income countries”. However, several authors suggest which coverage and quality of the North Brazilian region datasets is poor in regard south region, for example (Please, check this manuscripts: https://pubmed.ncbi.nlm.nih.gov/31800858/; https://pubmed.ncbi.nlm.nih.gov/31859881/).

Please consider exclude the following stretch “All DATASUS information follows the ethical precepts of the Declaration of Helsinki, so that users' anonymity is respected.”, because the study is based in secondary data.

How the authors dealt with the number of readmissions?

If the quality of data from DATASUS is considered high in Brazil why the authors did not use the breast cancer Brazilian estimates?

The Healthcare Access and Quality (HAQ) Index may have been influenced by the poor-quality data of the north region cities. Are the north region estimates reliable?

Reviewer #6: This study highlights an important topic on the impact of physical inactivity on hospitalization costs due to breast cancer, through secondary analysis of national databases. The study aimed “to estimate the economic burden of breast cancer due to physical inactivity in the Brazilian female population over a three-year period (2015 to 2017) and to relate these costs to conditions of access and quality of health services in Brazilian states”.

I have several major and some minor observations.

1) A first concern is using the VIGITEL database to estimate the prevalence of physical inactivity of Brazilians. This database is restricted to the Brazilian population aged ≥ 18 years living in households served by at least one fixed telephone line in 26 Brazilian capitals and the Federal District. Then, it is not representative of the Brazilian population, primarily because the exposure investigated (physical activity) can differ significantly between female residents of capitals and other cities in the country. The title, abstract, analyses, results, and conclusion should be revised to attend to this particularity.

2) In the Abstract, the author stated that the “Population Attributable Fraction” (PAF) was calculated but did not present the results, an important result of this study.

3) In the Introduction (lines 61-67), it stated some cost estimates of breast cancer in different countries and, importantly, in different points of time (from 2007 to 2020). This difference in time could be influencing in the estimates presented. I suggest considering presenting more current data and standardize the values in dollars.

4) In the Methods (lines 97-112), the databases used in the present study should be presented more clearly. Which data were obtained from DATAUS (SIH?) and which data were obtained from VIGITEL surveys? Are DATASUS and VIGITEL different databases with specific aims?

5) In lines 99-100, the author stated that “the quality of data from DATASUS is considered high and close to high-income countries”, but the references used to support this claim (11,12) deal whit mortality statistics' information, not included in this study. Please review this claim and references.

6) In lines 129-132, it is stated the data extracted from the DATASUS (total number of hospitalizations and the cost of these hospitalizations in the Brazilian female population aged 20-59 years and ≥60 years, according to year). In lines 325-326, the author informs that analyses were conducted at the country's geographic region and states and not at municipality level. It is unclear to me why the analyses were not restricted to 26 Brazilian capitals and the Federal District?

7) The RR used to estimate the attributable fraction was taken from a systematic review (Kyu 2013) (lines 192-195) that led to studies conducted in developed countries with populations different from the Brazilian one (United States, Canada, European countries, Japan and China). This limitation should be pointed out in the discussion.

8) Please consider presenting the results by capitals and Federal District, not by Brazilian states.

9) Lines 299-300. The statistic used (Spearman's correlation coefficient) was not described in the Method.

10) In lines 320-321, it is stated that “few estimated costs due to breast cancer [7]”. Please consider to cite other studies, such as Ding, 2016 (ref 9).

11) In lines 366-370, the author stated that “[…] physical activity promotion programs can be implemented, which will prevent breast cancer and other non-communicable diseases and conditions.” Despite the recognized importance of these programs, they do not guarantee the prevention of all breast cancer cases, given the existence of other risk factors for the disease.

12) It would be great if the author could include a limitation about the susceptibility of the analysis conducted in the present study to ecological fallacy.

13) Please change FAP (lines 251 and 379) by PAF.

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Reviewer #1: No

Reviewer #2: Yes: João Pedreira Duprat Neto

Reviewer #3: Yes: Jonas Baltazar Daniel ( Biologist, MSc Nutrition Food & Health, PhD candidate -Public Health)

Reviewer #4: No

Reviewer #5: No

Reviewer #6: No

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Attachments

Attachment

Submitted filename: PONE-D-21-09895_reviewer_19.05.21 to send.pdf

PONE-D-21-09895R1

Hospitalization cost related to breast cancer due to physical inactivity in the Brazilian state capitals

PLOS ONE

Dear,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please read the reviewer comments given below

Please submit your revised manuscript by12th August 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #4: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #4: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #4: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #4: Thanks to the author for his availability to answer the questions asked by the reviewers. As for the manuscript, essential questions remain that still need to be clarified.

1. When re-reading the manuscript, after adjustments, it is not clear to the reader the reason for analyzing only hospital expenses and only expenses in capitals and DF. For most cancers, including breast cancer, ambulatory (outpatient) costs are much higher than hospital (inpatient) costs. Why not analyze both expenses? Why analyze only spending in capitals and DF? Wouldn't the expenses in the UF be more significant than in the capitals? Was the choice made for greater ease, convenience, or the availability in data collection, or is there any other reason?

2. The usefulness of presenting breast cancer incidence (number and raw rate) and hospitalization (number and age-standardized rate) data are not convincing. Where was this data used in the manuscript? What is the need for four tables to present unused data?

3. It is unclear what is the usefulness of using the HAQ Index. There is no mention of a theoretical or empirical association between this indicator and the prevalence of physical inactivity in the introduction. What premise or assumption motivated the author to include this analysis?

4. In the reference article by Kyu et al. (2016), the RR varies according to activity level. Compared with less active women (reporting less than 600 MET minutes/week of total physical activity), the risk of breast cancer among those in the low active (600-3999 MET minutes), moderately active (4000-7999 MET minutes), and highly active (≥8000 MET minutes) categories were, respectively, reduced by 3%, 6%, and 14%. The author used Vigitel's physically inactive women as a category of prevalence analysis. This category corresponds to how many METs/minutes/week? The impression is that the correct category of choice for Vigitel would be "insufficient physical activity" and not "physically inactive." Clarify this question, please.

5. According to the 2018 WCRF report on physical activity and cancer risk, physical activity has been associated with postmenopausal breast cancer (C50 for women 50 years or older). Why were all women included?

6. The methodology section needs to be better organized and written. The suggestion is to divide the section into four subsections: study design, hospital cost data, RR and prevalence of physical inactivity, and data analysis. The study design is a cost-of-illness study to estimate the direct costs of breast cancers attributable to lack of physical activity from the perspective of the Brazilian SUS. This approach uses aggregated disease costs, and attributable population fraction (PAF) estimates to calculate the costs attributable to a given risk factor. Hospital cost data should inform the data source and how they were collected (this information is already contained in the latest version of the manuscript). The RR and prevalence subsection should inform where the values ​​were taken from. In the case of prevalence, the data source, the eligible population, and how the METS of the selected population were calculated need to be precise. Data analysis should inform how the PAF (equation) was calculated, the variables included in the equation, how the PAF was applied to expenses, and which software was used to calculate the final amounts.

7. Results must prioritize spending.

8. The reason for separating expenditures into 20-59 years and ≥ 60 years does not seem adequate. There are no restrictions on physical activity for those over 65s in the latest version of the WHO physical activity guide (2020). Therefore, any policy, program, or action involving physical activity will have the same recommendation regardless of premenopausal or postmenopausal women.

It is appropriate to analyze spending only in postmenopausal women since, according to WCRF, physical activity is related to postmenopausal breast cancer.

9. The discussion and conclusion sections should be rewritten in light of the above recommendations.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #4: No

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PONE-D-21-09895R2Hospitalization and ambulatory costs related to breast cancer due to physical inactivity in the Brazilian state capitalsPLOS ONE

Dear,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. 

Please submit your revised manuscript by 1st November 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #4: All comments have been addressed

Reviewer #7: (No Response)

Reviewer #8: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #4: Yes

Reviewer #7: Partly

Reviewer #8: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

Reviewer #7: No

Reviewer #8: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #4: Yes

Reviewer #7: Yes

Reviewer #8: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #4: Yes

Reviewer #7: Yes

Reviewer #8: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #4: I have only a final commentary. The author said that periodic exams prevent breast cancer (lines 315-316): "it is necessary that cities invest in other initiatives for the prevention of breast cancer, such as periodic exams." It's not true. Periodic exams such as mammography, contrary to routine cervical cancer exams that lower cervical cancer cases, increase the number of breast cancers.

Reviewer #7: The topic is of great public health importance. But it only focused on description of the situation. It should be very informative to the reader and policy makers. So, higher order statistics should be included. Sound study participants categorization should be include.

Reviewer #8: (No Response)

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Reviewer #4: No

Reviewer #7: No

Reviewer #8: No

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Attachments

Attachment

Submitted filename: review II.doc

Hospitalization and ambulatory costs related to breast cancer due to physical inactivity in the Brazilian state capitals

PONE-D-21-09895R3

Dear,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #4: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #4: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #4: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #4: No